Using PCR to Pre-emptively Treat Invasive Aspergillosis

Lewis White, Principal Clinical Scientist, Public Health Wales Microbiology, Cardiff and Rosemary Barnes, Emeritus Professor of Medical Microbiology, Cardiff University and former honorary Consultant Microbiologist at Public Health Wales address this important subject.

Aspergillus is an opportunistic fungus, harmless to the majority of the population but it infects immunocompromised individuals and patients with pre-existing lung conditions and causes a spectrum of diseases collectively known as aspergillosis. Acute invasive aspergillosis requires urgent treatment and leads to the highest degree of morbidity and mortality in high-risk patients and is, therefore, the focus of molecular diagnostic optimisation efforts.

Clinical scientists at the UK Clinical Mycology Network (UKCMN) Regional Mycology Reference Laboratory, Public Health Wales (PHW), are pioneering the use of rapid Aspergillus polymerase chain reaction (PCR) tests for earlier detection of Aspergillus, with the potential to reduce morbidity and mortality in patients at high risk of invasive aspergillosis.

The symptoms of invasive aspergillosis are non-specific and conventional diagnostics are slow with poor sensitivity, so clinicians commonly prescribe broad-spectrum empirical antifungal treatment, which often exposes the patient to unnecessary medication with potential side effects and high cost. UK antifungal expenditure is estimated to be over £100 million a year and rising.

Currently, PCR-based diagnostics can be used for two objectives: ruling out aspergillosis during a screening strategy in high-risk immunocompromised patients, or ruling in a diagnosis of invasive aspergillosis in patients with suspected disease.

Pioneering PCR

At the forefront of diagnostic mycological research, Dr Lewis White – Clinical Scientist – and Professor Rosemary Barnes – Honorary Consultant Microbiologist – at the PHW Regional Mycology Reference Laboratory, use their PCR assay for Aspergillus detection and diagnosis. The laboratory’s goals are two-fold: to reduce the number of patients receiving unnecessary empirical and long-term antifungal treatment, and to pre-emptively treat high-risk patients for aspergillosis before the disease clinically manifests. Professor Barnes describes the challenges in the field which spurred the laboratory’s interest in this work:

“Historically, when a patient was prescribed antifungal medication, that person would stay on treatment for much longer than necessary. Not only does this drive up costs, but has an impact on patient wellbeing.”

Due to the success of the project, the PHW Trust accepted Aspergillus PCR as a workable test and it is now fully ingrained into the trust’s service contracts with local hospitals. Constant audits are conducted to show an improvement in service and over the years, the laboratory has shown improved PCR standardisation, Professor Barnes describes these improvements:

“We have also gone one stage further: we no longer have to wait for a patient who is positive by multiple biomarkers to develop clinical signs of aspergillosis. We treat them pre-emptively on the basis of targeting infection rather than overt disease..”

Figure 1: Diagram outlining the different strategies to manage patients at risk of invasive aspergillosis at the Regional Mycology Reference Laboratory, Public Health Wales, Cardiff, Wales¹. Evaluating the use of PCR

“The difficulty we have in the clinical setting is that we’re never going to know how long an Aspergillus infection has been persisting as a sub-clinical presentation, post-exposure” explains Dr White, continuing: “Neither do we know when the patient was exposed and or exactly when the overt disease presented.

Since the implementation of regular weekly testing of high risk patients with PCR and biomarker tests (see Figure 1 for protocol), the laboratory has reduced its instance of overt invasive fungal disease by 75 per cent because of using pre-emptive treatment.